A Fatal Case of Valproate-Induced Hyperammonemic Encephalopathy
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International Journal of Epilepsy 4 (2017) 181–183 Contents lists available at ScienceDirect International Journal of Epilepsy journal homepage: http://www.journals.elsevier.com/ int ernational-journal-of-epilepsy Case report A fatal case of valproate-induced hyperammonemic encephalopathy: An update on proposed pathogenic mechanisms and treatment options a, b a a Yeung Gloria Wai Yue *, Chau Kei Wai , Woo Yat Ming Peter , Wong Hoi Tung , a Chan Kwong Yau a Department of Neurosurgery, Kwong Wah Hospital, 25 Waterloo Road, Hong Kong Special Administrative Region b Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region A R T I C L E I N F O Article history: Received 24 May 2017 Accepted 13 September 2017 Available online 14 September 2017 1. Introduction Valproate was selected as it is the only widely available broad spectrum antiepileptic proven to be similar to phenytoin in the Sodium valproate is widely used in a range of disorders control of status epilepticus and for its lower risk of drug including seizures, psychiatric conditions and chronic pain interference with the metabolism of nimodipine. By the third syndromes. Although it has a relatively favourable safety profile, day, the patient demonstrated significant neurological recovery to it is associated with severe idiosyncratic adverse effects, the most a GCS 13 and serial CTB showed hematoma resolution. A notable being valproate-induced hyperammonemic encephalopa- subsequent catheter angiogram did not reveal any intracranial thy (VHE), a rare phenomenon with fewer than 150 cases vascular lesion. A valproate dose of 1 200 mg/day (18 mg/kg/day) 1 documented in the last 10 years. The clinical presentation of was continued with satisfactory seizure control. 2,3 VHE may be subtle and if left untreated also fatal. This case On day ten, the patient became progressively lethargic with a report illustrates the importance early recognition and manage- rapid decline in consciousness to a GCS of 3 over six hours. ment of this rare and lethal adverse effect. Recurrent seizures were not observed and an electroencephalo- gram revealed normal bilateral symmetrical 8–12 Hz alpha 2. Case report rhythms. A CTB did not reveal evidence of rebleeding or infarction. Blood tests including parenchymal liver enzymes levels (aspartate A 71-year-old female, with known hypertension and Child- transaminase and alanine transaminase) were normal and the Pugh A Hepatitis B viral chronic liver disease was admitted for serum valproate level was within the therapeutic range at sudden expressive dysphasia. Upon admission the patient’s 423 mmol/L (347–693 mmol/L). However, the patient’s serum Glasgow Coma Scale (GCS) score was 11. Initial blood results ammonia level was markedly elevated at 378 mmol/L (10– including liver function were within normal limits. A computed 47 mmol/L), eight times the upper normal limit. tomography brain scan (CTB) revealed a left frontal lobar In view of suspected VHE, valproate was immediately intracerebral hematoma measuring 2.3 cm x 1.5 cm x 2.5 cm (vol- discontinued. However, this led to rebound status epilepticus that ume: 4.5 ml) and Sylvian fissure subarachnoid hemorrhage (SAH). required intravenous midazolam, propofol and phenytoin for Soon after admission, the patient developed status epilepticus. control. A subsequent CTB showed diffused cerebral edema and the She was mechanically ventilated and resuscitated. In addition to patient’s serum ammonia level rose to 411 mmol/L. Continuous the administration of intravenous midazolam, sodium valproate veno-venous hemofiltration was started and the ammonia level (400 mg, eight-hourly) was administered with successful cessation was subsequently reduced to 84 mmol/L. The patient failed to of seizures. In view of a suspected ruptured intracranial aneurysm recover consciousness and experienced septic shock secondary to and the risk of delayed ischemic neurological deficit, early systemic hospital acquired pneumonia. Although broad-spectrum anti- nimodipine was started according to our institution’s protocol. biotics were administered, she developed multi-organ failure and succumbed on day thirteen of admission. A post-mortem microscopic examination of the liver failed to show features of * Corresponding author. active inflammation or drug-induced liver injury (DILI). E-mail address: [email protected] (G.W.Y. Yeung). http://dx.doi.org/10.1016/j.ijep.2017.09.002 2213-6320/© 2017 Published by Elsevier, a division of RELX India, Pvt. Ltd on behalf of Indian Epilepsy Society. 182 G.W.Y. Yeung et al. / International Journal of Epilepsy 4 (2017) 181–183 3. Discussion Valproate-induced hyperammonemia is a relative common phenomenon with a highly variable incidence, occurring in 16 to 2,4 100% of patients. The majority of patients with isolated elevations of ammonia are asymptomatic with normal liver 4 function and are therefore often left unnoticed. In contrast, symptomatic valproate-induced hyperammonemia manifesting as encephalopathy is relatively uncommon. The symptoms of VHE are protean and include impaired consciousness, confusion, focal 2,3 neurological deficit and seizures. Unfortunately, few clinicians are aware of this rare, but potentially reversible drug-related condition. Several factors have been identified to be associated with the development of VHE. The concomitant use of sedatives and other anti-epileptic drugs has been shown to enhance valproate 1,2 toxicity. In addition, patients with a documented history of hereditary or dietary carnitine deficiencies or urea cycle enzyme 2,5 Fig. 1. Proposed mechanism for hyperammonemia due to valproic acid action in deficiencies are also susceptible. But apart from these factors, it hepatocytes. is generally difficult to predict individual risk. Understanding of this complication is further limited by its idiosyncratic nature. VHE 3.2. Mechanisms for valproate-induced hyperammonemic has been reported to occur in patients with a previous uneventful 6 encephalopathy exposure to valproate. In addition, no association between the 4,6 duration or dose of valproate with VHE was observed. With a Cytosolic ammonia, accumulated within astrocytes and maintenance dose of 18 mg/kg/day (the recommended adult daily neuronal cells, is first conjugated with glutatmate to form dosages are 1 000 to 2 000 mg; 10 to 30 mg/kg) our patient did not 6,11 glutamine by glutamine synthetase. The derived glutamine receive a particularly high dose of valproate. Affected patients have is transported to the mitochondria where it is then reverted back been prescribed a wide range of valproate dosing regimens with to ammonia by mitochondrial glutaminase. The excess ammonia resulting serum levels either above or within the therapeutic range 1,2 in the mitochondrial matrix leads to an increased production of as in our case. reactive oxygen species, which upregulates mitochondrial per- Valproate is widely known to cause DILI that is readily meability transition pore and cell membrane aquaporin channel characterized histologically by the presence of acute hepatitis, 7 expression. The oxidative stress consequently elicits to mito- cholestasis and steatosis. But evidence suggests that VHE often 6,11 chondrial swelling and cytotoxic edema. The binding of develops in the absence of acute liver injury, as illustrated by the ammonia with alpha-ketoglutarate can also inhibit extracellular normal serum liver function and post-mortem findings in our 4 glutamate reuptake resulting in NMDA receptor pathway patient. This suggests the existence of alternate pathogenic 5,6,9,11 mediated excitotoxicity. See Fig. 2. mechanisms for hyperammonemia. 3.3. Treatment considerations 3.1. Mechanisms for valproate-induced hyperammonemia Upon diagnosis of VHE, immediate discontinuation of valproate Although the exact pathogenesis of VHE is not well understood, is mandatory and complete recovery may be possible without 5 several key mechanisms involving hepatic and renal metabolic additional treatment. Founded upon the postulation that hepatic pathways have been proposed. carnitine depletion contributes to valproate-induced hyperammo- nemia, there have been reports describing the clinical benefits of intravenous levo-carnitine supplementation in VHE patients by 3.1.1. Hepatic pathway 9,109,10] promoting beta-oxidation and ammonia metabolism. N- Valproate is theorized to disrupt hepatic ammonia metabolism 8 carbamylglutamate, a synthetic analog of NAG, has also been and the urea cycle through carnitine and co-enzyme A depletion. Carnitine, an essential co-factor in mitochondrial beta-oxidation, binds with valproate and is sequestered and then excreted. Depleted carnitine stores prevents the uptake of fatty acids into the mitochondria and limits the production of N-acetylglutamate (NAG), the required activator of the first enzyme in the urea cycle, carbamoyl-phosphate-synthetase I (CPS I). This reduction of mitochondrial beta-oxidation causes a metabolic shift to cytosolic omega-oxidation. The accumulation of omega-oxidative metabo- lites further reduces ammonia breakdown, notably through the 9,10 inhibitory action of propionic acid on CPS I. See Fig. 1. 3.1.2. Renal pathway It is hypothesized that valproate stimulates kidney tubule glutaminase that subsequently enhances glutamine uptake into renal cortical cell mitochondria. The conversion of glutamine to 10 glutamate ultimately leads to increased ammonia production. Fig. 2. Proposed mechanism of astrocyte swelling and dysfunction in hyperam- monemia.